CORRESPONDENCE

 

Response to 'Commentary on the published position statement regarding the pathogenesis of fetal basal ganglia-thalamic hypoxic-ischaemic injury' (Anthony et al.)

 

 

To the Editor: We thank Anthony et al. for their response to our review and position statement.^[1] To start, we need to correct the respondents' remark that our position statement was intended for the use of 'defence experts in cerebral palsy (CP) litigation cases'. In fact, we wrote that it was 'for obstetricians engaged as experts in CP litigation'. We offered a fair and evidence-based summary, based on pertinent peer-reviewed research on humans. The aim was to help experts assist South African (SA) courts, irrespective of whether they are instructed by plaintiff or defendant representatives.

We cited five original research works in humans that showed positive associations between acute profound hypoxic-ischaemic (HI) brain insult and basal ganglia-thalamus (BGT) pattern injury on imaging.^[2-6] A sixth source, the landmark work of Nakao et al^[7] from 2022, is considered by the respondents to be of limited value. On the association between sudden-onset fetal bradycardia and BGT lesions found in Nakao et al., the respondents write that the 'data to support these various contentions are not evident from the published material'. This is incorrect. The data are in the text and in accompanying figures and tables. The weight of evidence in the six cited works supports the association between acute profound HI brain insult and BGT pattern injury. The evidence reasonably fulfils seven of Bradford Hill's nine causal criteria - strength of association, consistency, specificity, temporality, plausibility, coherence and experiment.^[8] Consistency is especially strong, with the same direction of association across all studies. The respondents have added no new research works to reduce our confidence in this association. The only divergent original research is that of Smith et al.^[9] (co-authored by six of the respondents), which has methodological deficiencies, as has previously been pointed out.^[10]

The respondents take issue with our terminology for perinatal sentinel events (PSEs), considering it 'oxymoronic' to describe certain PSEs as 'concealed'. For greater clarity, we could instead have used 'not contemporaneously clinically identifiable'. An example is sudden intrapartum kinking of a non-prolapsed umbilical cord, as included by Sie et al.^[4] as a possible PSE. Such an event would show only on cardiotocography as sustained bradycardia of sudden onset. Intrapartum cardiotocography is of course not routine in SA practice, being mandatory in high-risk labour only. Such events do not display dramatic maternal collapse, intrapartum haemorrhage or cord prolapse. Our review showed that 'concealed' PSEs are frequent antecedents of intrapartum HI injuries, especially considering the results of Nakao et al.^[11] from 2020. Restricting the definition of PSE to a list (not necessarily a definition) given in the American College of Obstetricians and Gynecologists/American Academy of Pediatrics (ACOG/AAP) document^[12] on neonatal encephalopathy makes no pathophysiological sense. What matters is whether the fetus experiences a sustained HI insult of sudden onset, irrespective of whether the cause is clinically obvious. The respondents misrepresent the findings of Shankaran et al.^[5] on the association of BGT injuries with PSEs, writing that the authors found no significant difference in BGT injuries between cases with and without PSEs. However, Shankaran et al. calculated a p-value of 0.03 for this difference, indicating statistical significance, and noted the higher frequency of BGT injury in infants with PSEs in their abstract, results and discussion.

The respondents introduce a recent research contribution on perinatal BGT pattern injuries by Misser et al.,^[13] who establish perirolandic cortex involvement as an integral part of the BGT pattern injury, preferring to use the epithet 'Rolandic-basal ganglia-thalamus (RBGT)'. Our position statement on perirolandic involvement aligns with the descriptions of Misser et al. Selected case summaries are provided by Misser et al., which are incorrectly reported by the respondents. For example, only 9% (not 27%) of births followed failed operative vaginal delivery in cases with massive paramedian injury. Misser et al. include a 'mixed RBGT + watershed pattern' in their classification of magnetic resonance imaging patterns of HI injury. We are aware of this subgroup and do not, as the respondents believe, see BGT and watershed patterns as 'immiscible'.

The respondents suggest that BGT pattern injury results from a predictable, discoverable, gradual-onset HI insult, unless there is an overt PSE as listed in the ACOG/AAP document. Their evidence for this comes not from original research data, but from interpretation of three opinion sources: the ACOG/AAP document,^[12] Volpes Neurology of the Newborn textbook,^[14] and an opinion article by Wisnowski et al.^[15] We have dealt with the respondents' use of these three sources in our review. These are respected sources, but they cover broad topics without sharp focus on timing and mode of causation of BGT pattern injury. They also cannot match original human research data for strength of evidence. In our review, we covered two narrative review articles that were sufficiently focused,^[16,17] and our position statement is largely in line with their authors' findings.

While accepting priming as possibly contributory in HI injury, the respondents dispute our concern that antepartum factors 'may result in fetal priming, leading to vulnerability to BGT injury by relatively mild hypoxic insults'. Our concern, that this 'may' occur, is based on published evidence.^[18-24] For example, late-onset fetal growth restriction is a priming disorder easily missed in the antepartum period, leaving the fetus without reserve in the hypoxic-centric intrapartum process.^[23,24] The modern approach in fetal medicine tries to identify priming factors in the antepartum period to determine the timing and mode of delivery. Other examples are recurrent maternal infections,^[20-22] umbilical cord abnormalities and fetomaternoplacental hypoperfusion,^[11] metabolic disorders^[25] and genetic predispositions.^[25-28] To deny fetal priming in the aetiology of neonatal encephalopathy and cerebral palsy is to deny the modern approach to prevent adverse perinatal outcomes. Exclusive focus on intrapartum factors is fundamentally flawed. Techniques to identify primed fetuses include sonographic estimation of the cerebroplacental ratio,^[24] and assessment of biomarkers such as soluble fms-like tyrosine kinase-1 and placental growth factor.^[29] Reasonable certainty on scientific causality can only be achieved after holistic exhaustive assessment of each case, including antepartum, intrapartum and neonatal exposures.

No new data or opinion have been provided by the respondents for us to rethink any of the points in our position statement. We respectfully urge Anthony et al. to carefully evaluate the applicable scientific literature on causation of BGT pattern HI brain injury.

The position paper^[1] has been endorsed by the Expert Opinion Panel of the South African Society of Obstetricians and Gynaecologists (SASOG).

I Bhorat

Subdepartment of Fetal Medicine, Department of Obstetrics and Gynaecology, Faculty of Health Sciences, University of KwaZulu-Natal, Durban, South Africa. bhorat@worldonline.co.za

E Buchmann

Department of Obstetrics and Gynaecology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

K Frank

Department of Obstetrics and Gynaecology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

P Soma-Pillay

Department of Obstetrics and Gynaecology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa

E Nicolaou

Division of Fetal Medicine, Department of Obstetrics and Gynaecology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

L Pistorius

Division of Fetal Medicine, Department of Obstetrics and Gynaecology, Stellenbosch University, Cape Town, South Africa

I Smuts

Department of Paediatric Neurology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa

 

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